Cardiac amyloidosis


Cardiac amyloidosis is a subcategory of amyloidosis where there is the depositing of the protein amyloid in the cardiac muscle and surrounding tissues. Amyloid, a misfolded and insoluble protein, can become a deposit in the heart’s atria, valves, or ventricles. These deposits can cause thickening of different sections of the heart, leading to decreased cardiac function. The multisystemic disease was often misdiagnosed, with diagnosis previously occurring after death during the autopsy. However, recent advancements of technologies have increased the diagnosis of the disease. This disease has multiple types including light chain, familial, and senile. One of the most studied types is light chain cardiac amyloidosis. The prognosis depends on the extent of the deposits in the body and the type of amyloidosis.

Types

Light chain (AL-CM)

The formation of amyloid is due to these free light chains circulating through the body, caused by abnormal clones of plasma cells overproducing monoclonal immunoglobulin lambda light chains. This type usually affects males over the age of 60 and is rapidly progressive. Diagnostic tests includes serum and urine electrophoresis, laboratory testing for the determination of elevated levels of troponin and BNP, and ECGs showing low QRS voltages.

Familial (ATTRm-CM)

This type is caused by mutations of proteins involved in amyloid formation, including transthyretin, fibrinogen, apolipoprotein A1, or apolipoprotein A2. A common mutation is the TTR gene mutation Val122Ile. This type of amyloidosis can be identified by genetic testingfor protein mutation. Familial amyloidosis symptoms are centered around neuropathological and cardiac problems.

Senile (ATTRwt-CM)

This type is considered the wild-type mutation which leads to the development of TTR deposits. It usually affects males over 70 years with the manifestation of carpal tunnel syndrome. This type is often misdiagnosed, however, greater use of cardiac magnetic resonance has increased diagnosing rates.

Symptoms

Amyloid deposition in the heart can cause both diastolic and systolic heart failure.
Symptoms of cardiac amyloidosis include dyspnea on exertion, peripheral edema, ascites, thromboembolisms, and symmetric, sensory neuropathy, postural hypotension, periorbital bleeding, pericardial effusion, atrial arrhythmia, first/second degree heart blocks, atrial fibrillation, syncope, elevated neck veins and jugular venous pressure.
For patients with light-chain amyloidosis, there is possibility of macroglossia, periorbital bruising, and loss of the third and fourth heart sound.

Cause

The general cause of cardiac amyloidosis is misfolding of a specific protein precursor depending on the amyloidosis type. Protein precursors include immunoglobulin-derived light chains and transthyretin mutations. The misfolding of the protein causes it to have insoluble beta-pleated sheets, creating an amyloid. Amyloid, the aggregation, or clumping, of proteins, is resistant to degradation by the body. Amyloids are mostly fibrils, while also containing a P component, apolipoprotein, collagen, fibronectin, and laminin. The P component, a pentameric protein, stabilizes the fibrils of the amyloid, which reduces their clearance from the body. Deposits of the amyloids can occur through out of the body, including the heart, liver, kidneys, spleen, adrenal glands, and bones. Deposits in the extracellular cardiac space can stiffen the heart, resulting in restriction of the ventricles.

Diagnosis

Echocardiography

is used to provide an assessment of the heart’s function. Amyloidosis presents with ventricle and valvular thickening, biatrial enlargement, restrictive filling pattern, with normal to mildly reduced systolic function and decreased diastolic filling.
Echocardiography, can be used to help physicians with diagnosis, however, it can only be used for the suggesting of the disease not the confirmation, unless it is late stage amyloidosis.

ECG/EKG

of patients with cardiac amyloidosis usually show a low voltage in the limb leads with unusual, extreme right axis. There is usually a normal P-wave, however, it can be slightly prolonged. For patients with light-chain amyloidosis, the QRS complex pattern is skewed, with poor R-waves of the chest leads.
Holter ECGs can be used to identify asymptomatic arrhythmias.
EKG changes may be present, showing low voltage and conduction abnormalities like atrioventricular block or sinus node dysfunction.

Laboratory tests

Laboratory tests including urea and creatinine levels, liver enzymes, glucose, thyroid function, full blood count, and clotting tests. The analysis of serum and urine for presence of monoclonal immunoglobulin is also done through immunofixation for detection of the monoclonal band. Presence of the monoclonal band would be consistent with light chain amyloidosis. For light chain amyloidosis, serum immunoglobulin free light chain assay can be used for diagnosis and following of the amyloidosis. In light-chain amyloidosis, a low paraprotein level can be present.

Cardiac biomarkers

Biomarkers of troponins and N-terminal of BNP would be elevated with patients with cardiac amyloidosis.

Biopsies

Extracardiac biopsies of tissues of the kidney, liver, peripheral nerve, or abdominal fat can be used to confirm the presence of amyloid deposits. Amyloid deposits in biopsy samples are confirmed through the use of Congo red dye, which produces a green birefringence when viewed under a polarized light. Sirius red staining or electron microscopy examination can also be done. The determination of the type of amyloid can be done by immunohisto-labeling techniques as well as immunofluorescence staining.
For light-chain amyloidosis patients, bone marrow biopsies could be conducted to determine baseline percentage of plasma cells and to rule out multiple myeloma.

Catherization

is the test used to test for elevated diastolic ventricular pressures. This test is more invasive and would be performed after inconclusive endomyocardial biopsy samples.

Cardiac magnetic resonance imaging

is capable of measuring the thickness of different areas of the heart. This can be used for quantification of the deposits in the heart. CMR also shows the characterization of myocardial tissue through patterns of gadolinium enhancements. However, none of the CMR technique is able to differentiate ATTR-CM and AL-CM definitely.
For AL-CM, 68% of them have symmetrical and concentric left ventricular hypertrophy. On the other hand, for ATTR-CM, 79% of them have asymmetrical left ventricular hypertrophy and 18% of them have symmetrical and concentric left ventricular hypertrophy.
In T1-weighted imaging, oedema in the heart can be detected with a high T1 signal. Meanwhile, enlargement of heart cells will reduce the T1 signal. Using T1 signal, Extracellular volume is useful to determine the degree of amyloid deposition around the heart cells and detect the regression of amyloid deposits after treatment. ECV is higher in ATTR-CM than in AL-CM.
In T2-weighted imaging, the T2 signal is increased in acute myocarditis, and myocardial infarction. T2 signal is also increased in AL-CM and ATTR-CM but the signal is greater in AL-CM before starting chemotherapy.
Late gadolinum enhancement can determine the severity of deposition of amyloid in heart tissue. The higher the LGE signal, the more severe the heart involvement. It can be divided into three stages: no LGE, subendocardial LGE, and full-thickness LGE.

Scintigraphy/radionuclide imaging

can be used to measure the extent and distribution of the amyloid throughout the body, including the liver, kidney, spleen, and heart. A radiolabelled serum amyloid P component can be administered to a patient intravenously and the P component pools to the amyloid deposit proportional to the size of the deposit. The labelling of the P component can then be pictured by a gamma camera.

Mass spectrometry

can be used to determine whether the protein is light-chain or familial amyloidosis by identifying the protein subunit.

Prognosis

Prognosis of cardiac amyloidosis is correlated to the extent of the cardiac dysfunction. Usually the prognosis is not good and aggressive treatments are needed. Worse outcomes have been seen when echocardiography shows left ventricular wall thickness, poor systolic function and severe diastolic dysfunction.
For light-chain amyloidosis early detection leads to best possibility of therapies prolonging the period of remission. Prognosis can be made by looking at the levels of cardiac biomarkers troponin I, troponin T, BNP, and NT-proBNP.

Treatments

Treatments differ according to type of amyloidosis present.
For light-chain amyloidosis, the use of FLC assays and NT-proBNP levels can be used to monitor the progression of amyloidosis and any response to treatments. Treatments targeting plasma cells to eliminate the misfolded free light chains can be done, such as chemotherapy for amyloidogenic plasma cell dyscrasia. Drugs can be prescribed including midodrine for autonomic neuropathy, amiodarone for patients with atrial fibrillation to prevent arrhythmias, and warfarin used after a cardioembolic episode. Beta-blockers should be avoided due to the usual symptom of hypotension. Treatments are also focused on treating the patient's heart failure.
For familial amyloidosis, ACE-inhibitors and beta-blockers can be prescribed if there is no autonomic neuropathy.
There is inconclusive data regarding the use of pacemakers and implantable cardioverter defibrillators as useful treatments for amyloidosis.